Background Patients with unresectable stage III non-small cell lung cancer (NSCLC) have an unmet need for new therapies that improve survival. This phase III trial investigated the safety and efficacy of concurrent ociperlimab and tislelizumab plus concurrent chemoradiotherapy (cCRT) in treatment-naïve patients with stage III NSCLC.Methods In this phase III, multicenter, randomized, multiarm, open-label trial, patients with unresectable stage III NSCLC received concurrent ociperlimab plus tislelizumab and cCRT, followed by ociperlimab plus tislelizumab (arm A), tislelizumab and cCRT, followed by tislelizumab (arm B), or cCRT, followed by durvalumab (arm C) (NCT04866017). Objectives were to compare progression-free survival (PFS), overall survival (OS), objective response rate (ORR), duration of response, disease control rate, clinical benefit rate, time to death or distant metastasis (TTDM), and safety and tolerability for arms A versus C, B versus C, and A versus B.Results 63 patients were randomized to arms A (N=22), B (N=19), and C (N=22) prior to early trial termination. In A, B, and C, respectively, 95.5% (21/22), 84.2% (16/19), and 95.5% (21/22) were current or former smokers, and 68.2% (15/22), 73.7% (14/19), and 68.2% (15/22) had PD-L1 expression in tumor cells of ≥1%. Median PFS (95% CI) was not reached (NR) (6.3–not estimable (NE)) in A, 15.0 months (7.4 to NE) in B, and 10.4 months (5.7 to NE) in C. Median OS and TTDM were NR in any arm. ORR (95% CI) was 68.2% (45.1%–86.1%) in A, 68.4% (43.4%–87.4%) in B, and 59.1% (36.4%–79.3%) in C; all responses were partial responses. Treatment-emergent adverse events (TEAEs) occurred in all patients; in arms A, B, and C, respectively, pneumonitis occurred in 18.2% (4/22), 5.6% (1/18), and 9.1% (2/22) of patients, and interstitial lung disease occurred in 13.6% (3/22), 11.1% (2/18), and 0% of patients, of which the majority of events for each were grade 1/2. Grade ≥3 treatment-related TEAEs occurred in 68.2% (15/22), 66.7% (12/18), and 68.2% (15/22) of patients in arms A, B, and C, respectively.Conclusions There was a trend toward improved efficacy when adding tislelizumab with or without ociperlimab to cCRT followed by tislelizumab with or without ociperlimab compared with cCRT followed by durvalumab; however, efficacy data were for descriptive purposes only. No unexpected or new safety signals were identified.
Breast cancer is the leading cause of cancer death for women worldwide, with triple-negative breast cancer (TNBC) considered one of the most aggressive sub-types and accounting for ∼15-20% of all cases. Unfortunately, there remains an unmet medical need for effective and well-tolerated treatments for advanced/metastatic TNBC, particularly for patients who have received a prior standard-of-care topoisomerase-1 inhibitor (topo-1) ADC. In heavily pretreated patients, standard-of-care single-agent chemotherapy has limited efficacy, with response rates of ∼5%, median PFS ∼7 weeks, median OS ∼6.7 months. Emiltatug ledadotin (Emi-Le; XMT-1660) is a B7-H4-directed Dolasynthen ADC designed with a precise, target-optimized drug-to-antibody ratio (DAR 6) and a proprietary auristatin F-HPA microtubule inhibitor payload with controlled bystander effect. The FDA has granted Emi-Le two Fast Track designations for the treatment of adult patients with certain breast cancers, including patients with advanced or metastatic TNBC and patients with advanced or metastatic HER-2 low / HER-2 negative breast cancer who have previously been treated with topo-1 ADCs. As of March 8, 2025 data cutoff, treatment was generally well tolerated in the dose escalation portion of the ongoing Phase 1 trial. In patients with TNBC dosed with 38.1-67.4 mg/m2 per cycle, the most common TRAEs were transient AST increase (43%, G3 18%), fatigue (32%, G3 0%), typically asymptomatic proteinuria (30%, G3 7%), and nausea (27%, G3 2%). In patients with B7-H4 high TNBC dosed with 38.1-67.4 mg/m2 per cycle dose range, all of whom were heavily pretreated and had received at least one prior topo-1 ADC, interim clinical data demonstrated: 23% (3/13) confirmed response rate overall; 29% (2/7) in patients with ≤4 prior lines in locally advanced/metastatic setting; a preliminary median PFS of 16 weeks (6.1, NR) and a median OS not yet reached in patients with ≤4 prior lines in the locally advanced/metastatic setting. Based on these encouraging clinical activity and tolerability data, the expansion portion (EXP) of the Phase 1 trial has been initiated and is actively enrolling patients with TNBC who have received 1-4 prior lines of systemic therapy in the advanced/metastatic setting, including at least one topo-1 ADC. EXP has a Simon 2-stage design and will evaluate two dosing regimens: 67.4 mg/m2 Q4W or 80 mg/m2 Q4W with a 44.5 mg/m2 loading dose on days 1 and 8 of the first 4-week cycle. Patients are being evaluated for B7-H4 expression by IHC and are stratified into B7-H4 TPS “high” and B7-H4 TPS “low” cohorts. NCT05377996 N. Abuhadra, A. Giordano, K. M. Kalinsky, H. Han, N. P. McAndrew, A. I. Spira, K. C. Kelley, J. A. O'Shaughnessy, D. Starks, N. Chan, R. Parajuli, G. M. Wulf, A. Chaudhry, J. S. Wang, F. Meric-Bernstam, A. Tiersten, A. M. Weise, D. L. Richardson, P. A. Robinson, L. A. Huppert, C. Rogalski, N. Zizlsperger, A. Reske, E. P. Hamilton. Emiltatug Ledadotin (Emi-Le): A B7-H4-Directed Dolasynthen Antibody-Drug Conjugate (ADC) Being Investigated in Phase 1 Dose Expansion in Patients with Triple Negative Breast Cancer who Received at Least One Prior Topoisomarase-1 Inhibitor ADC [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS1-08-23.
Background The phase II FRACTION-Lung platform trial (NCT02750514) aimed to evaluate novel immunotherapy combinations in advanced non-small-cell lung cancer (aNSCLC). Patients and methods Adults with aNSCLC and Eastern Cooperative Oncology Group performance status ≤1 were allocated to tracks 1 to 5 based on programmed cell death protein (ligand) 1 [PD-(L)1] status and/or prior receipt of anti-PD-(L)1 therapy, and received nivolumab (anti-PD-1) as monotherapy or combination therapy [dasatinib (multi-kinase inhibitor), ipilimumab (anti-CTLA-4), relatlimab (anti-LAG-3), or linrodostat (IDO1 inhibitor)]. Patients with progression in one arm could be re-randomized. Primary endpoints were objective response rate (ORR); duration of response (DOR); and 24-week progression-free survival (PFS) rate. Safety was a secondary endpoint; biomarker analyses were exploratory. Results Overall, 295 patients were treated (191 received no prior immunotherapy, 118 received prior immunotherapy; 14 were re-randomized assigned). Among patients without prior immunotherapy, ORRs ranged from 0% (multiple arms) to 25% (nivolumab plus ipilimumab: 3/12 patients; nivolumab plus dasatinib: 1/4 patients), and among patients with prior immunotherapy from 2.3% (nivolumab plus linrodostat: 1/43 patients) to 5.6% (nivolumab plus ipilimumab: 1/18 patients). Median DOR was not estimated due to limited tumor responses. Twenty-four-week PFS rates ranged from 30.2% [nivolumab-only (n = 40)] to 45.5% [nivolumab plus ipilimumab (n = 12)] among patients without prior immunotherapy and 11.1% [nivolumab plus linrodostat (n = 43)] to 19.1% [nivolumab plus dasatinib (n = 41)] among patients with prior immunotherapy. No new safety signals were observed. Small sample sizes in each treatment group limited analyses, including biomarkers. The study was discontinued early due to an evolving treatment landscape and limited efficacy signals. Given the rolling, adaptive design, this trial was not statistically powered to assess treatment benefits and draw definitive efficacy conclusions, as early termination and the changing standard of care limited accrual. Conclusions Despite limited efficacy, the innovative adaptive trial design allowed rapid evaluation of multiple regimens, which may inform future trials.
Oncogenic mutations in PIK3CA are present in approximately 40% of HR+/HER2- BC and define a validated target for therapeutic inhibition in this setting. Approved inhibitors yield modest efficacy in combination with endocrine therapy (ET) due to dose-limiting toxicities associated with non-selective PI3K inhibition. RLY-2608 is the first oral, pan-mutant-selective, allosteric α-selective PI3K inhibitor (PI3Kαi) designed to overcome these limitations. The FIH ReDiscover (NCT05216432) study investigated RLY-2608 + fulvestrant (F) in pts with PIK3CA-mutant, HR+/HER2- BC who had been previously treated with CDK4/6i and ET. Here, we report subgroup efficacy analyses according to baseline characteristics, including prior selective estrogen receptor degrader (SERD) treatment and ESR1 mutation status. Previously treated adult pts with evaluable HR+/HER2- advanced BC and PIK3CA mutation per local assessment were eligible. Pts received the RP2D of RLY-2608 (600 mg BID fasted) + standard-dose F. Key objectives were investigator-assessed efficacy per RECIST v1.1 and adverse events (AEs) per CTCAE v5.0. Objective response rate (ORR) is defined as the rate of any confirmed complete or partial response (CR or PR). Progression-free survival (PFS) is defined as the time from date of first dose to the date of progression per RECIST v1.1 or death by any cause in the absence of progression. Tumor response in pts with measurable disease and PFS in pts with evaluable disease, without detectable PTEN/AKT co-alterations, were assessed according to baseline characteristics including prior treatment history (prior SERD vs no prior SERD) and presence of ESR1 mutation. PIK3CA and ESR1 ctDNA were assessed at baseline and at C2D1 of study treatment as a pharmacodynamic marker of biologic activity. Safety was assessed in all pts. As of 26MAR25, 64 pts with evaluable disease were treated with the RP2D of RLY-2608 + F. Efficacy was evaluated in the subgroup of 52 pts without detectable PTEN/AKT co-alterations, of whom 42% received ≥2 prior systemic therapies for advanced BC; 52% had received any prior SERD; 31% had detectable ESR1 mutation at baseline. 31/52 pts had measurable disease with 12/31 achieving an objective response (ORR 38.7%, 95% CI 21.8-57.8) and 25/31 (80.6%) experiencing any radiographic tumor reduction. Of 31 pts with measurable disease, 16 received prior SERD with 7/16 achieving a confirmed PR (ORR 43.8%, 95% CI 19.8-70.1). In the 10 pts with measurable disease who had detectable ESR1 mutation at baseline, 6 achieved a confirmed PR (ORR 60.0%, 95% CI 26.2-87.8). Across all 52 pts treated at the RP2D, mPFS was 10.3 mo (95% CI 7.2-18.4). In 27 pts who received prior SERD, the mPFS was 11.0 mo (5.6 NR), and in 16 pts with detectable ESR1 mutation at baseline the mPFS was 8.8 mo (95% CI 3.0-18.4). 97% of pts with paired results experienced decline or clearance of PIK3CA ctDNA across genotypes, and all of those with ESR1 mutation at baseline and paired results experienced ctDNA decline or clearance. Treatment-related AEs (TRAEs) were generally low-grade, manageable, and reversible. Hyperglycemia, when reported, was low grade with most pts not requiring medication management. Severe stomatitis and rash were absent or rare. There were no grade 4/5 TRAEs. RLY-2608 + F demonstrates promising efficacy in pts with PIK3CA-mutated HR+/HER2- advanced BC who have progressed on CDK4/6i. These data also highlight the activity of RLY-2608 in pts with prior exposure and resistance to SERD where benefit from fulvestrant is not expected, and support the ongoing pivotal investigation of RLY-2608 + F. C. Saura, G. Curigliano, A. Italiano, E. Felip, A. Schram, P. Tolosa, A. Schott, B. Pistilli, A. Guerrero Zotano, S. Ehsani, K. Wisinski, R. Nanda, J. McGuinness, M. Wei, J. Liu, V. Debien, A. Marra, K. Jhaveri, S. Isakoff, S. Loi, L. Schwartzberg, K. Yeung, M. George, E. Hamilton, C. Perez, C. Ma, N. Unni, J. Rodon, A. Spira, E. Puente-Poushnejad, A. Wagner, L. Xu, D. Havkins, F. Ramirez, S. Landergan, G. Tan, A. Timm, E. Kwak, D. Bergstrom, S. Sammons, A. Varkaris. Efficacy of mutant-selective PI3Kα inhibitor RLY-2608 in combination with fulvestrant in patient (pt) subset populations, including pts with PIK3CA-mutant HR+/HER2- advanced breast cancer (BC) pre-treated with fulvestrant or other SERD [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PD10-07.
3011 Background: BMS-986504 selectively binds to the PRMT5-MTA complex, which represents a synthetic lethal target in MTAP -del cancer cells, while sparing MTAP– wild-type cells. In the first-in-human phase 1/2 CA240-0007 study in advanced, unresectable or metastatic solid tumors with homozygous MTAP -del, BMS-986504 was found to be well tolerated and demonstrated antitumor activity in multiple tumors. Here, we report clinical results and the first PK and PD analyses of BMS-986504 from the dose escalation and expansion phases of CA240-0007. Methods: Pts with measurable/evaluable disease and no available treatment (Tx) with curative intent were enrolled; 7 doses were evaluated (50 to 800 mg) in dose escalation. Objective response rate (ORR), disease control rate (DCR), duration of response (DOR), time to response (TTR), safety, PK, PD, including plasma SDMA were assessed. Results: As of 2 Dec 24, 152 heavily pretreated pts were enrolled across all doses: NSCLC (n = 34), PDAC (n = 41), cholangiocarcinoma (n = 12), and mesothelioma (n = 12) were the most common tumor types. With a median f/u of 9.0 mo (95% CI 7.6–9.9), continued durable antitumor activity and deepening tumor regression were seen across tumor types and doses (ORR = 23%, DCR = 70%, median DOR = 10.5 mo, TTR = 4.6 mo). No new safety signals were identified. Most Tx-related adverse events (TRAEs) were grade (Gr) 1 or 2; 13% had Gr ≥ 3 TRAEs (Gr 3 = 12%, Gr 4 = < 1%, Gr 5 = 0). Doses from 50 to 600 mg QD were assessed for PK/PD. The AUC (0-24) after multiple doses was approximately dose proportional at 200 to 600 mg, and the terminal t 1/2 after a single dose was approximately 24 h (table). There were dose-dependent reductions in predicted plasma SDMA, with the 400 and 600 mg doses approaching the plateau. Conclusions: With longer f/u, BMS-986504 continued to show increasingly durable antitumor activity. BMS-986504 demonstrated a favorable PK/PD profile, supporting QD dosing at 400 and 600 mg. These results support further investigation of BMS-986504 at 400 and 600 mg QD as a potential first-in-class synthetic lethal Tx option in pts with advanced solid tumors with MTAP -del. Clinical trial information: NCT05245500 . PK and PD. 50 mg QD 100 mg QD 200 mg QD 400 mg QD 600 mg QD PK after multiple doses t max a (min–max), h 2.0 (2.0–4.0)n = 3 2.0 (1.0–2.0)n = 3 2.0 (0.5–6.0)n = 8 2.0 (0.5–4.0)n = 10 2.0 (1.0–6.0)n = 10 C max , b ng/mL 107n = 3 377n = 3 685n = 8 1240n = 10 2110n = 10 AUC (0-24) , b h∙ng/mL 948 n = 3 3060 n = 3 7150 n = 7 11,800n = 10 26,700n = 9 AUC (0-24) , b,c h∙ng/mL/mg 19.0n = 3 30.6n = 3 35.8n = 7 29.5n = 10 44.6n = 9 Terminal t 1/2 after single dose, d h 21.7 n = 1 80.7 n = 1 21.5 n = 14 21.7 n = 14 24.1 n = 1 PD Translational exposure targets (C avgss ), X 0.08 0.21 0.5 1.1 1.7 Predicted plasma SDMA reduction, a % (90% PI) 30.0 (23.2–37.8) 38.8 (27.1–47.5) 48.3 (42.0–53.0) 55.0 (50.7–57.6) 57.4 (54.3–59.0) a Median. b Geometric mean. c Dose-normalized. d Arithmetic mean.
